Delivery of compounds for the treatment of Parkinson&#39;s through an inhalation route

ABSTRACT

The present invention relates to the delivery of antiparkinsons drugs through an inhalation route. In a method aspect of the present invention, an antiparkinsons drug is administered to a patient through an inhalation route. The method comprises: a) heating a thin layer of an antiparkinsons drug on a solid support to form a vapor; and, b) passing air through the heated vapor to produce aerosol particles having less than 5% drug degradation products. In a kit aspect of the present invention, a kit for delivering an antiparkinsons drug through an inhalation route is provided which comprises: a) a thin coating of a an antiparkinsons drug composition; and, b) a device for dispending said thin coating as a condensation aerosol.

This application is a continuation of U.S. patent application Ser. No.10/816,567, filed Apr. 1, 2004, now U.S. Pat. No. 7,052,680; which is acontinuation of U.S. patent application Ser. No. 10/153,139, filed May20, 2002, now U.S. Pat. No. 6,814,954; which claims priority to U.S.provisional application Ser. No. 60/294,203 entitled “Thermal VaporDelivery of Drugs,” filed May 24, 2001, Rabinowitz and Zaffaroni, theentire disclosure of which is hereby incorporated by reference. Thisapplication further claims priority to U.S. provisional application Ser.No. 60/317,479 entitled “Aerosol Drug Delivery,” filed Sep. 5, 2001,Rabinowitz and Zaffaroni, the entire disclosure of which is herebyincorporated by reference. Each of the foregoing applications isincorporated herein by reference in their entirety.

FIELD OF THE INVENTION

The present invention relates to the delivery of compounds for thetreatment of Parkinsons through an inhalation route. Specifically, itrelates to aerosols containing antiparkinsonian drugs that are used ininhalation therapy.

BACKGROUND OF THE INVENTION

There are a number of compositions currently marketed for the treatmentof Parkinsons. The compositions contain at least one active ingredientthat provides for observed therapeutic effects. Among the activeingredients given in such antiparkinsoniam compositions arebenzotropine, pergolide, ropinerole, amantadine and deprenyl.

It is desirable to provide a new route of administration forantiparkinsonian drugs that rapidly produces peak plasma concentrationsof the compounds. The provision of such a route is an object of thepresent invention.

SUMMARY OF THE INVENTION

The present invention relates to the delivery of compounds for thetreatment of Parkinsons through an inhalation route. Specifically, itrelates to aerosols containing antiparkinsonian drugs that are used ininhalation therapy.

In a composition aspect of the present invention, the aerosol comprisesparticles comprising at least 5 percent by weight of an antiparkinsoniandrug. Preferably, the particles comprise at least 10 percent by weightof an antiparkinsonian drug. More preferably, the particles comprise atleast 20 percent, 30 percent, 40 percent, 50 percent, 60 percent, 70percent, 80 percent, 90 percent, 95 percent, 97 percent, 99 percent,99.5 percent or 99.97 percent by weight of an antiparkinsonian drug.

Typically, the aerosol has a mass of at least 10 μg. Preferably, theaerosol has a mass of at least 100 μg. More preferably, the aerosol hasa mass of at least 0.200 μg.

Typically, the particles comprise less than 10 percent by weight ofantiparkinsonian drug degradation products. Preferably, the particlescomprise less than 5 percent by weight of antiparkinsonian drugdegradation products. More preferably, the particles comprise less than2.5, 1, 0.5, 0.1 or 0.03 percent by weight of antiparkinsonian drugdegradation products.

Typically, the particles comprise less than 90 percent by weight ofwater. Preferably, the particles comprise less than 80 percent by weightof water. More preferably, the particles comprise less than 70 percent,60 percent, 50 percent, 40 percent, 30 percent, 20 percent, 10 percent,or 5 percent by weight of water.

Typically, at least 50 percent by weight of the aerosol is amorphous inform, wherein crystalline forms make up less than 50 percent by weightof the total aerosol weight, regardless of the nature of individualparticles. Preferably, at least 75 percent by weight of the aerosol isamorphous in form. More preferably, at least 90 percent by weight of theaerosol is amorphous in form.

Typically, the aerosol has an inhalable aerosol particle density greaterthan 10⁶ particles/mL. Preferably, the aerosol has an inhalable aerosolparticle density greater than 10⁷ particles/mL or 10⁸ particles/mL.

Typically, the aerosol particles have a mass median aerodynamic diameterof less than 5 microns, e.g., 0.2 to 3 microns. Preferably, theparticles have a mass median aerodynamic diameter of less than 3microns. More preferably, the particles have a mass median aerodynamicdiameter of less than 2 or 1 micron(s).

Typically, the geometric standard deviation around the mass medianaerodynamic diameter of the aerosol particles is less than 3.0.Preferably, the geometric standard deviation is less than 2.5. Morepreferably, the geometric standard deviation is less than 2.3.

Typically, the aerosol is formed by heating a composition containing anantiparkinsonian drug to form a vapor and subsequently allowing thevapor to condense into an aerosol.

In another composition aspect of the present invention, the aerosolcomprises particles comprising at least 5 percent by weight ofbenzotropine, pergolide, ropinerole, amantadine or deprenyl. Preferably,the particles comprise at least 10 percent by weight of benzotropine,pergolide, ropinerole, amantadine or deprenyl. More preferably, theparticles comprise at least 20 percent, 30 percent, 40 percent, 50percent, 60 percent, 70 percent, 80 percent, 90 percent, 95 percent, 97percent, 99 percent, 99.5 percent or 99.97 percent by weight ofbenzotropine, pergolide, ropinerole, amantadine or deprenyl.

Typically, the aerosol has a mass of at least 10 μg. Preferably, theaerosol has a mass of at least 100 μg. More preferably, the aerosol hasa mass of at least 200 μg.

Typically, the particles comprise less than 10 percent by weight ofbenzotropine, pergolide, ropinerole, amantadine or deprenyl degradationproducts. Preferably, the particles comprise less than 5 percent byweight of benzotropine, pergolide, ropinerole, amantadine or deprenyldegradation products. More preferably, the particles comprise less than2.5, 1, 0.5, 0.1 or 0.03 percent by weight of benzotropine, pergolide,ropinerole, amantadine or deprenyl degradation products.

Typically, the particles comprise less than 90 percent by weight ofwater. Preferably, the particles comprise less than 80 percent by weightof water. More preferably, the particles comprise less than 70 percent,60 percent, 50 percent, 40 percent, 30 percent, 20 percent, 10 percent,or 5 percent by weight of water.

Typically, at least 50 percent by weight of the aerosol is amorphous inform, wherein crystalline forms make up less than 50 percent by weightof the total aerosol weight, regardless of the nature of individualparticles. Preferably, at least 75 percent by weight of the aerosol isamorphous in form. More preferably, at least 90 percent by weight of theaerosol is amorphous in form.

Typically, where the aerosol comprises benzotropine, the aerosol has aninhalable aerosol drug mass density of between 0.1 mg/L and 4 mg/L.Preferably, the aerosol has an inhalable aerosol drug mass density ofbetween 0.2 mg/L and 3 mg/L. More preferably, the aerosol has aninhalable aerosol drug mass density of between 0.3 mg/L and 2 mg/L.

Typically, where the aerosol comprises pergolide, the aerosol has aninhalable aerosol drug mass density of between 0.01 mg/L and 2.5 mg/L.Preferably, the aerosol has an inhalable aerosol drug mass density ofbetween 0.02 mg/L and 1 mg/L. More preferably, the aerosol has aninhalable aerosol drug mass density of between 0.05 mg/L and 0.5 mg/L.

Typically, where the aerosol comprises ropinerole, the aerosol has aninhalable aerosol drug mass density of between 0.02 mg/L and 4 mg/L.Preferably, the aerosol has an inhalable aerosol drug mass density ofbetween 0.04 mg/L and 2 mg/L. More preferably, the aerosol has aninhalable aerosol drug mass density of between 0.10 mg/L and 1.0 mg/L.

Typically, where the aerosol comprises amantadine, the aerosol has aninhalable aerosol drug mass density of between 5 mg/L and 500 mg/L.Preferably, the aerosol has an inhalable aerosol drug mass density ofbetween 10 mg/L and 200 mg/L. More preferably, the aerosol has aninhalable aerosol drug mass density of between 20 mg/L and 150 mg/L.

Typically, where the aerosol comprises deprenyl, the aerosol has aninhalable aerosol drug mass density of between 0.5 mg/L and 12.5 mg/L.Preferably, the aerosol has an inhalable aerosol drug mass density ofbetween 1 mg/L and 10 mg/L. More preferably, the aerosol has aninhalable aerosol drug mass density of between 2 mg/L and 7.5 mg/L.

Typically, the aerosol has an inhalable aerosol particle density greaterthan 10⁶ particles/mL. Preferably the aerosol has an inhalavle aerosolparticle density greater than 10⁷ particles/mL or 10⁸ particles/mL.

Typically, the aerosol particles have a mass median aerodynamic diameterof less than 5 microns, e.g., 0.2 to 3 microns. Preferably, theparticles have a mass median aerodynamic diameter of less than 3microns. More preferably, the particles have a mass median aerodynamicdiameter of less than 2 or 1 micron(s).

Typically, the geometric standard deviation around the mass medianaerodynamic diameter of the aerosol particles is less than 3.0.Preferably, the geometric standard deviation is less than 2.5. Morepreferably, the geometric standard deviation is less than 2.3.

Typically, the aerosol is formed by heating a composition containingbenzotropine, pergolide, ropinerole, amantadine or deprenyl to form avapor and subsequently allowing the vapor to condense into an aerosol.

In a method aspect of the present invention, an antiparkinsonian drug isdelivered to a mammal through an inhalation route. The method comprises:a) heating a composition, wherein the composition comprises at least 5percent by weight of an antiparkinsonian drug, to form a vapor; and, b)allowing the vapor to cool, thereby forming a condensation aerosolcomprising particles, which is inhaled by the mammal. Preferably, thecomposition that is heated comprises at least 10 percent by weight of anantiparkinsonian drug. More preferably, the composition comprises atleast 20 percent, 30 percent, 40 percent, 50 percent, 60 percent, 70percent, 80 percent, 90 percent, 95 percent, 97 percent, 99 percent,99.5 percent, 99.9 percent or 99.97 percent by weight of anantiparkinsonian drug.

Typically, the particles comprise at least 5 percent by weight of anantiparkinsonian drug. Preferably, the particles comprise at least 10percent by weight of an antiparkinsonian drug. More preferably, theparticles comprise at least 20 percent, 30 percent, 40 percent, 50percent, 60 percent, 70 percent, 80 percent, 90 percent, 95 percent, 97percent, 99 percent, 99.5 percent, 99.9 percent or 99.97 percent byweight of an antiparkinsonian drug.

Typically, the condensation aerosol has a mass of at least 10 μg.Preferably, the aerosol has a mass of at least 100 μg. More preferably,the aerosol has a mass of at least 200μ.

Typically, the particles comprise less than 10 percent by weight ofantiparkinsonian drug degradation products. Preferably, the particlescomprise less than 5 percent by weight of antiparkinsonian drugdegradation products. More preferably, the particles comprise 2.5, 1,0.5, 0.1 or 0.03 percent by weight of antiparkinsonian drug degradationproducts.

Typically, the particles comprise less than 90 percent by weight ofwater. Preferably, the particles comprise less than 80 percent by weightof water. More preferably, the particles comprise less than 70 percent,60 percent, 50 percent, 40 percent, 30 percent, 20 percent, 10 percent,or 5 percent by weight of water.

Typically, at least 50 percent by weight of the aerosol is amorphous inform, wherein crystalline forms make up less than 50 percent by weightof the total aerosol weight, regardless of the nature of individualparticles. Preferably, at least 75 percent by weight of the aerosol isamorphous in form. More preferably, at least 90 percent by weight of theaerosol is amorphous in form.

Typically, the particles of the delivered condensation aerosol have amass median aerodynamic diameter of less than 5 microns, e.g., 0.2 to 3microns. Preferably, the particles have a mass median aerodynamicdiameter of less than 3 microns. More preferably, the particles have amass median aerodynamic diameter of less than 2 or 1 micron(s).

Typically, the geometric standard deviation around the mass medianaerodynamic diameter of the aerosol particles is less than 3.0.Preferably, the geometric standard deviation is less than 2.5. Morepreferably, the geometric standard deviation is less than 2.3.

Typically, the delivered aerosol has an inhalable aerosol particledensity greater than 10⁶ particles/mL. Preferably, the aerosol has aninhalable aerosol particle density greater than 10⁷ particles/mL or 10⁸particles/mL.

Typically, the rate of inhalable aerosol particle formation of thedelivered condensation aerosol is greater than 10⁸ particles per second.Preferably, the aerosol is formed at a rate greater than 10⁹ inhalableparticles per second. More preferably, the aerosol is formed at a rategreater than 10¹⁰ inhalable particles per second.

Typically, the delivered condensation aerosol is formed at a rategreater than 0.5 mg/second. Preferably, the aerosol is formed at a rategreater than 0.75 mg/second. More preferably, the aerosol is formed at arate greater than 1 mg/second, 1.5 mg/second or 2 mg/second.

Typically, the delivered condensation aerosol results in a peak plasmaconcentration of an antiparkinsonian drug in the mammal in less than 1h. Preferably, the peak plasma concentration is reached in less than 0.5h. More preferably, the peak plasma concentration is reached in lessthan 0.2, 0.1, 0.05, 0.02, 0.01, or 0.005 h (arterial measurement).

In another method aspect of the present invention, one of benzotropine,pergolide, ropinerole, amantadine or deprenyl is delivered to a mammalthrough an inhalation route. The method comprises: a) heating acomposition, wherein the composition comprises at least 5 percent byweight of benzotropine, pergolide, ropinerole, amantadine or deprenyl,to form a vapor; and, b) allowing the vapor to cool, thereby forming acondensation aerosol comprising particles, which is inhaled by themammal. Preferably, the composition that is heated comprises at least 10percent by weight of benzotropine, pergolide, ropinerole, amantadine ordeprenyl. More preferably, the composition comprises at least 20percent, 30 percent, 40 percent, 50 percent, 60 percent, 70 percent, 80percent, 90 percent, 95 percent, 97 percent, 99 percent, 99.5 percent,99.9 percent or 99.97 percent by weight of benzotropine, pergolide,ropinerole, amantadine or deprenyl.

Typically, the particles comprise at least 5 percent by weight ofbenzotropine, pergolide, ropinerole, amantadine or deprenyl. Preferably,the particles comprise at least 10 percent by weight of benzotropine,pergolide, ropinerole, amantadine or deprenyl. More preferably, theparticles comprise at least 20 percent, 30 percent, 40 percent, 50percent, 60 percent, 70 percent, 80 percent, 90 percent, 95 percent, 97percent, 99 percent, 99.5 percent, 99.9 percent or 99.97 percent byweight of benzotropine, pergolide, ropinerole, amantadine or deprenyl.

Typically, the condensation aerosol has a mass of at least 10 μg.Preferably, the aerosol has a mass of at least 100 μg. More preferably,the aerosol has a mass of at least 200 μg.

Typically, the particles comprise less than 10 percent by weight ofbenzotropine, pergolide, ropinerole, amantadine or deprenyl degradationproducts. Preferably, the particles comprise less than 5 percent byweight of benzotropine, pergolide, ropinerole, amantadine or deprenyldegradation products. More preferably, the particles comprise 2.5, 1,0.5, 0.1 or 0.03 percent by weight of benzotropine, pergolide,ropinerole, amantadine or deprenyl degradation products.

Typically, the particles comprise less than 90 percent by weight ofwater. Preferably, the particles comprise less than 80 percent by weightof water. More preferably, the particles comprise less than 70 percent,60 percent, 50 percent, 40 percent, 30 percent, 20 percent, 10 percent,or 5 percent by weight of water.

Typically, at least 50 percent by weight of the aerosol is amorphous inform, wherein crystalline forms make up less than 50 percent by weightof the total aerosol weight, regardless of the nature of individualparticles. Preferably, at least 75 percent by weight of the aerosol isamorphous in form. More preferably, at least 90 percent by weight of theaerosol is amorphous in form.

Typically, the particles of the delivered condensation aerosol have amass median aerodynamic diameter of less than 5 microns, e.g., 0.2 to 3microns. Preferably, the particles have a mass median aerodynamicdiameter of less than 3 microns. More preferably, the particles have amass median aerodynamic diameter of less than 2 or 1 micron(s).

Typically, the geometric standard deviation around the mass medianaerodynamic diameter of the aerosol particles is less than 3.0.Preferably, the geometric standard deviation is less than 2.5. Morepreferably, the geometric standard deviation is less than 2.3.

Typically, where the aerosol comprises benzotropine, the deliveredaerosol has an inhalable aerosol drug mass density of between 0.1 mg/Land 4 mg/L. Preferably, the aerosol has an inhalable aerosol drug massdensity of between 0.2 mg/L and 3 mg/L. More preferably, the aerosol hasan inhalable aerosol drug mass density of between 0.3 mg/L and 2 mg/L.

Typically, where the aerosol comprises pergolide, the delivered aerosolhas an inhalable aerosol drug mass density of between 0.01 mg/L and 2.5mg/L. Preferably, the aerosol has an inhalable aerosol drug mass densityof between 0.02 mg/L and 1 mg/L. More preferably, the aerosol has aninhalable aerosol drug mass density of between 0.05 mg/L and 0.5 mg/L.

Typically, where the aerosol comprises ropinerole, the delivered aerosolhas an inhalable aerosol drug mass density of between 0.02 mg/L and 4mg/L. Preferably, the aerosol has an inhalable aerosol drug mass densityof between 0.04 mg/L and 2 mg/L. More preferably, the aerosol has aninhalable aerosol drug mass density of between 0.10 mg/L and 1.0 mg/L.

Typically, where the aerosol comprises amantadine, the delivered aerosolhas an inhalable aerosol drug mass density of between 5 mg/L and 500mg/L. Preferably, the aerosol has an inhalable aerosol drug mass densityof between 10 mg/L and 200 mg/L. More preferably, the aerosol has aninhalable aerosol drug mass density of between 20 mg/L and 150 mg/L.

Typically, where the aerosol comprises deprenyl, the delivered aerosolhas an inhalable aerosol drug mass density of between 0.5 mg/L and 12.5mg/L. Preferably, the aerosol has an inhalable aerosol drug mass densityof between 1 mg/L and 10 mg/L. More preferably, the aerosol has aninhalable aerosol drug mass density of between 2 mg/L and 7.5 mg/L.

Typically, the delivered aerosol has an inhalable aerosol particledensity greater than 10⁶ particles/mL. Preferably, the aerosol has aninhalable aerosol particle density greater than 10⁷ particles/mL or 10⁸particles/mL.

Typically, the rate of inhalable aerosol particle formation of thedelivered condensation aerosol is greater than 10⁸ particles per second.Preferably, the aerosol is formed at a rate greater than 10⁹ inhalableparticles per second. More preferably, the aerosol is formed at a rategreater than 10¹⁰ inhalable particles per second.

Typically, the delivered condensation aerosol is formed at a rategreater than 0.5 mg/second. Preferably, the aerosol is formed at a rategreater than 0.75 mg/second. More preferably, the aerosol is formed at arate greater than 1 mg/second, 1.5 mg/second or 2 mg/second.

Typically, where the condensation aerosol comprises benzotropine,between 0.1 mg and 4 mg of benzotropine are delivered to the mammal in asingle inspiration. Preferably, between 0.2 mg and 3 mg of benzotropineare delivered to the mammal in a single inspiration. More preferably,between 0.3 mg and 2 mg of benzotropine are delivered to the mammal in asingle inspiration.

Typically, where the condensation aerosol comprises pergolide, between0.01 mg and 2.5 mg of pergolide are delivered to the mammal in a singleinspiration. Preferably, between 0.02 mg and 1 mg of pergolide aredelivered to the mammal in a single inspiration. More preferably,between 0.05 mg and 0.5 mg of pergolide are delivered to the mammal in asingle inspiration.

Typically, where the condensation aerosol comprises ropinerole, between0.02 mg and 4 mg of ropinerole are delivered to the mammal in a singleinspiration. Preferably, between 0.04 mg and 2 mg of ropinerole aredelivered to the mammal in a single inspiration. More preferably,between 0.1 mg and 1.0 mg of ropinerole are delivered to the mammal in asingle inspiration.

Typically, where the condensation aerosol comprises amantadine, between5 mg and 500 mg of amantadine are delivered to the mammal in a singleinspiration. Preferably, between 10 mg and 200 mg of amantadine aredelivered to the mammal in a single inspiration. More preferably,between 20 mg and 150 mg of amantadine are delivered to the mammal in asingle inspiration.

Typically, where the condensation aerosol comprises deprenyl, between0.5 mg and 12.5 mg of deprenyl are delivered to the mammal in a singleinspiration. Preferably, between 1 mg and 10 mg of deprenyl aredelivered to the mammal in a single inspiration. More preferably,between 2 mg and 7.5 mg of deprenyl are delivered to the mammal in asingle inspiration.

Typically, the delivered condensation aerosol results in a peak plasmaconcentration of benzotropine, pergolide, ropinerole, amantadine ordeprenyl in the mammal in less than 1 h. Preferably, the peak plasmaconcentration is reached in less than 0.5 h. More preferably, the peakplasma concentration is reached in less than 0.2, 0.1, 0.05, 0.02, 0.01,or 0.005 h (arterial measurement).

In a kit aspect of the present invention, a kit for delivering anantiparkinsonian through an inhalation route to a mammal is providedwhich comprises: a) a composition comprising at least 5 percent byweight of an antiparkinsonian drug; and, b) a device that forms anantiparkinsonian drug aerosol from the composition, for inhalation bythe mammal. Preferably, the composition comprises at least 20 percent,30 percent, 40 percent, 50 percent, 60 percent, 70 percent, 80 percent,90 percent, 95 percent, 97 percent, 99 percent, 99.5 percent, 99.9percent or 99.97 percent by weight of an antiparkinsonian drug.

Typically, the device contained in the kit comprises: a) an element forheating the antiparkinsonian drug composition to form a vapor; b) anelement allowing the vapor to cool to form an aerosol; and, c) anelement permitting the mammal to inhale the aerosol.

In another kit aspect of the present invention, a kit for deliveringbenzotropine, pergolide, ropinerole, amantadine or deprenyl through aninhalation route to a mammal is provided which comprises: a) acomposition comprising at least 5 percent by weight of benzotropine,pergolide, ropinerole, amantadine or deprenyl; and, b) a device thatforms a benzotropine, pergolide, ropinerole, amantadine or deprenylaerosol from the composition, for inhalation by the mammal. Preferably,the composition comprises at least 20 percent, 30 percent, 40 percent,50 percent, 60 percent, 70 percent, 80 percent, 90 percent, 95 percent,97 percent, 99 percent, 99.5 percent, 99.9 percent or 99.97 percent byweight of benzotropine, pergolide, ropinerole, amantadine or deprenyl.

Typically, the device contained in the kit comprises: a) an element forheating the benzotropine, pergolide, ropinerole, amantadine or deprenylcomposition to form a vapor; b) an element allowing the vapor to cool toform an aerosol; and, c) an element permitting the mammal to inhale theaerosol.

BRIEF DESCRIPTION OF THE FIGURE

FIG. 1 shows a cross-sectional view of a device used to deliverantiparkinsonian drug aerosols to a mammal through an inhalation route.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

“Aerodynamic diameter” of a given particle refers to the diameter of aspherical droplet with a density of 1 g/mL (the density of water) thathas the same settling velocity as the given particle.

“Aerosol” refers to a suspension of solid or liquid particles in a gas.

“Aerosol drug mass density” refers to the mass of an antiparkinsoniandrug per unit volume of aerosol.

“Aerosol mass density” refers to the mass of particulate matter per unitvolume of aerosol.

“Aerosol particle density” refers to the number of particles per unitvolume of aerosol.

“Amantadine” refers to tricylo[3.3.1.1^(3,7)]decan-1-amine.

“Amantadine degradation product” refers to a compound resulting from achemical modification of amantadine. The modification, for example, canbe the result of a thermally or photochemically induced reaction. Suchreactions include, without limitation, oxidation and hydrolysis. Anexample of a degradation product is nitroso-adamantane.

“Amorphous particle” refers to a particle that does not contain morethan 50 percent by weight of a crystalline form. Preferably, theparticle does not contain more than 25 percent by weight of acrystalline form. More preferably, the particle does not contain morethan 10 percent by weight of a crystalline form.

“Antiparkinsonian drug degradation product” refers to a compoundresulting from a chemical modification of an antiparkinsonian drug. Themodification, for example, can be the result of a thermally orphotochemically induced reaction. Such reactions include, withoutlimitation, oxidation and hydrolysis.

“Benzotropine” refers to3-(diphenylmethoxy)-8-methyl-8-azabicyclo[3.2.1]-octane.

“Benzotropine degradation product” refers to a compound resulting from achemical modification of benzotropine. The modification, for example,can be the result of a thermally or photochemically induced reaction.Such reactions include, without limitation, oxidation and hydrolysis.

“Condensation aerosol” refers to an aerosol formed by vaporization of asubstance followed by condensation of the substance into an aerosol.

“Deprenyl” refers to ®-(−)-N,2-dimethyl-N-2-propynylphenethylamine.

“Deprenyl degradation product” refers to a compound resulting from achemical modification of deprenyl. The modification, for example, can bethe result of a thermally or photochemically induced reaction. Suchreactions include, without limitation, oxidation and hydrolysis.

“Inhalable aerosol drug mass density” refers to the aerosol drug massdensity produced by an inhalation device and delivered into a typicalpatient tidal volume.

“Inhalable aerosol mass density” refers to the aerosol mass densityproduced by an inhalation device and delivered into a typical patienttidal volume.

“Inhalable aerosol particle density” refers to the aerosol particledensity of particles of size between 100 nm and 5 microns produced by aninhalation device and delivered into a typical patient tidal volume.

“Mass median aerodynamic diameter” or “MMAD” of an aerosol refers to theaerodynamic diameter for which half the particulate mass of the aerosolis contributed by particles with an aerodynamic diameter larger than theMMAD and half by particles with an aerodynamic diameter smaller than theMMAD.

“Pergolide” refers to 8-[(methylthio)methyl]-6-propylergoline.

“Pergolide degradation product” refers to a compound resulting from achemical modification of pergolide. The modification, for example, canbe the result of a thermally or photochemically induced reaction. Suchreactions include, without limitation, oxidation and hydrolysis. Anexample of a degradation product is 3-nitrophthalic acid.

“Rate of aerosol formation” refers to the mass of aerosolizedparticulate matter produced by an inhalation device per unit time.

“Rate of inhalable aerosol particle formation” refers to the number ofparticles of size between 100 nm and 5 microns produced by an inhalationdevice per unit time.

“Rate of drug aerosol formation” refers to the mass of aerosolizedantiparkinsonian drug produced by an inhalation device per unit time.

“Ropinerole” refers to4-[2-(dipropylamino)-ethyl]-1,3-dihydro-2H-indol-2-one.

“Ropinerole degradation product” refers to a compound resulting from achemical modification of ropinerole. The modification, for example, canbe the result of a thermally or photochemically induced reaction. Suchreactions include, without limitation, oxidation and hydrolysis.

“Settling velocity” refers to the terminal velocity of an aerosolparticle undergoing gravitational settling in air.

“Typical patient tidal volume” refers to 1 L for an adult patient and 15mL/kg for a pediatric patient.

“Vapor” refers to a gas, and “vapor phase” refers to a gas phase. Theterm “thermal vapor” refers to a vapor phase, aerosol, or mixture ofaerosol-vapor phases, formed preferably by heating.

Formation of Antiparkinsonian Drug Containing Aerosols

Any suitable method is used to form the aerosols of the presentinvention. A preferred method, however, involves heating a compositioncomprising an antiparkinsonian drug to form a vapor, followed by coolingof the vapor such that it condenses to provide an antiparkinsonian drugcomprising aerosol (condensation aerosol). The composition is heated inone of four forms: as pure active compound (e.g., pure benzotropine,pergolide, ropinerole, amantadine or deprenyl); as a mixture of activecompound and a pharmaceutically acceptable excipient; as a salt form ofthe pure active compound; and, as a mixture of active compound salt formand a pharmaceutically acceptable excipient.

Salt forms of antiparkinsonian drugs (e.g., benzotropine, pergolide,ropinerole, amantadine or deprenyl) are either commercially available orare obtained from the corresponding free base using well known methodsin the art. A variety of pharmaceutically acceptable salts are suitablefor aerosolization. Such salts include, without limitation, thefollowing: hydrochloric acid, hydrobromic acid, acetic acid, maleicacid, formic acid, and fumaric acid salts.

Pharmaceutically acceptable excipients may be volatile or nonvolatile.Volatile excipients, when heated, are concurrently volatilized,aerosolized and inhaled with the antiparkinsonian drug. Classes of suchexcipients are known in the art and include, without limitation,gaseous, supercritical fluid, liquid and solid solvents. The followingis a list of exemplary carriers within the classes: water; terpenes,such as menthol; alcohols, such as ethanol, propylene glycol, glyceroland other similar alcohols; dimethylformamide; dimethylacetamide; wax;supercritical carbon dioxide; dry ice; and mixtures thereof.

Solid supports on which the composition is heated are of a variety ofshapes. Examples of such shapes include, without limitation, cylindersof less than 1.0 mm in diameter, boxes of less than 1.0 mm thickness andvirtually any shape permeated by small (e.g., less than 1.0 mm-sized)pores. Preferably, solid supports provide a large surface to volumeratio (e.g., greater than 100 per meter) and a large surface to massratio (e.g., greater than 1 cm² per gram).

A solid support of one shape can also be transformed into another shapewith different properties. For example, a flat sheet of 0.25 mmthickness has a surface to volume ratio of approximately 8,000 permeter. Rolling the sheet into a hollow cylinder of 1 cm diameterproduces a support that retains the high surface to mass ratio of theoriginal sheet but has a lower surface to volume ratio (about 400 permeter).

A number of different materials are used to construct the solidsupports. Classes of such materials include, without limitation, metals,inorganic materials, carbonaceous materials and polymers. The followingare examples of the material classes: aluminum, silver, gold, stainlesssteel, copper and tungsten; silica, glass, silicon and alumina;graphite, porous carbons, carbon yarns and carbon felts;polytetrafluoroethylene and polyethylene glycol. Combinations ofmaterials and coated variants of materials are used as well.

Where aluminum is used as a solid support, aluminum foil is a suitablematerial. Examples of silica, alumina and silicon based materialsinclude amphorous silica S-5631 (Sigma, St. Louis, Mo.), BCR 171 (analumina of defined surface area greater than 2 m²/g from Aldrich, St.Louis, Mo.) and a silicon wafer as used in the semiconductor industry.Carbon yarns and felts are available from American Kynol, Inc., NewYork, N.Y. Chromatography resins such as octadecycl silane chemicallybonded to porous silica are exemplary coated variants of silica.

The heating of the antiparkinsonian drug compositions is performed usingany suitable method. Examples of methods by which heat can be generatedinclude the following: passage of current through an electricalresistance element; absorption of electromagnetic radiation, such asmicrowave or laser light; and, exothermic chemical reactions, such asexothermic solution, hydration of pyrophoric materials and oxidation ofcombustible materials.

Delivery of Antiparkinsonian Drug Containing Aerosols

Antiparkinsonian drug containing aerosols of the present invention aredelivered to a mammal using an inhalation device. Where the aerosol is acondensation aerosol, the device has at least three elements: an elementfor heating an antiparkinsonian drug containing composition to form avapor; an element allowing the vapor to cool, thereby providing acondensation aerosol; and, an element permitting the mammal to inhalethe aerosol. Various suitable heating methods are described above. Theelement that allows cooling is, in it simplest form, an inert passagewaylinking the heating means to the inhalation means. The elementpermitting inhalation is an aerosol exit portal that forms a connectionbetween the cooling element and the mammal's respiratory system.

One device used to deliver the antiparkinsonian drug containing aerosolis described in reference to FIG. 1. Delivery device 100 has a proximalend 102 and a distal end 104, a heating module 106, a power source 108,and a mouthpiece 110. An antiparkinsonian drug composition is depositedon a surface 112 of heating module 106. Upon activation of a useractivated switch 114, power source 108 initiates heating of heatingmodule 106 (e.g, through ignition of combustible fuel or passage ofcurrent through a resistive heating element). The antiparkinsonian drugcomposition volatilizes due to the heating of heating module 106 andcondenses to form a condensation aerosol prior to reaching themouthpiece 110 at the proximal end of the device 102. Air flow travelingfrom the device distal end 104 to the mouthpiece 110 carries thecondensation aerosol to the mouthpiece 110, where it is inhaled by themammal.

Devices, if desired, contain a variety of components to facilitate thedelivery of antiparkinsonian containing aerosols. For instance, thedevice may include any component known in the art to control the timingof drug aerosolization relative to inhalation (e.g., breath-actuation),to provide feedback to patients on the rate and/or volume of inhalation,to prevent excessive use (i.e., “lock-out” feature), to prevent use byunauthorized individuals, and/or to record dosing histories.

Dosage of Antiparkinsonian Drug Containing Aerosols

The dosage amount of antiparkinsonian drugs in aerosol form is generallyno greater than twice the standard dose of the drug given orally. Forinstance, benzotropine, pergolide, ropinerole, amantadine and deprenylare given orally at strengths of 0.5 mg to 2 mg, 0.05 mg to 1.0 mg, 0.25mg to 4 mg, 50 mg to 100 mg, and 5 mg respectively for the treatment ofParkinsons. As aerosols, 0.1 mg to 4 mg of benztropine, 0.01 mg to 2.5mg of pergolide, 0.02 mg to 4 mg of ropinerole, 5 mg to 250 mg ofamantadine, and 0.5 mg to 12.5 mg of deprenyl are generally provided perinspiration for the same indication. A typical dosage of anantiparkinsonian drug aerosol is either administered as a singleinhalation or as a series of inhalations taken within an hour or less(dosage equals sum of inhaled amounts). Where the drug is administeredas a series of inhalations, a different amount may be delivered in eachinhalation.

One can determine the appropriate dose of antiparkinsonian drugcontaining aerosols to treat a particular condition using methods suchas animal experiments and a dose-finding (Phase I/II) clinical trial.One animal experiment involves measuring plasma concentrations of drugin an animal after its exposure to the aerosol. Mammals such as dogs orprimates are typically used in such studies, since their respiratorysystems are similar to that of a human. Initial dose levels for testingin humans is generally less than or equal to the dose in the mammalmodel that resulted in plasma drug levels associated with a therapeuticeffect in humans. Dose escalation in humans is then performed, untileither an optimal therapeutic response is obtained or a dose-limitingtoxicity is encountered.

Analysis of Antiparkinsonian Drug Containing Aerosols

Purity of an antiparkinsonian drug containing aerosol is determinedusing a number of methods, examples of which are described in Sekine etal., Journal of Forensic Science 32:1271-1280 (1987) and Martin et al.,Journal of Analytic Toxicology 13:158-162 (1989). One method involvesforming the aerosol in a device through which a gas flow (e.g., airflow) is maintained, generally at a rate between 0.4 and 60 L/min. Thegas flow carries the aerosol into one or more traps. After isolationfrom the trap, the aerosol is subjected to an analytical technique, suchas gas or liquid chromatography, that permits a determination ofcomposition purity.

A variety of different traps are used for aerosol collection. Thefollowing list contains examples of such traps: filters; glass wool;impingers; solvent traps, such as dry ice-cooled ethanol, methanol,acetone and dichloromethane traps at various pH values; syringes thatsample the aerosol; empty, low-pressure (e.g., vacuum) containers intowhich the aerosol is drawn; and, empty containers that fully surroundand enclose the aerosol generating device. Where a solid such as glasswool is used, it is typically extracted with a solvent such as ethanol.The solvent extract is subjected to analysis rather than the solid(i.e., glass wool) itself. Where a syringe or container is used, thecontainer is similarly extracted with a solvent.

The gas or liquid chromatograph discussed above contains a detectionsystem (i.e., detector). Such detection systems are well known in theart and include, for example, flame ionization, photon absorption andmass spectrometry detectors. An advantage of a mass spectrometrydetector is that it can be used to determine the structure ofantiparkinsonian drug degradation products.

Particle size distribution of an antiparkinsonian drug containingaerosol is determined using any suitable method in the art (e.g.,cascade impaction). An Andersen Eight Stage Non-viable Cascade Impactor(Andersen Instruments, Smyrna, Ga.) linked to a furnace tube by a mockthroat (USP throat, Andersen Instruments, Smyrna, Ga.) is one systemused for cascade impaction studies.

Inhalable aerosol mass density is determined, for example, by deliveringa drug-containing aerosol into a confined chamber via an inhalationdevice and measuring the mass collected in the chamber. Typically, theaerosol is drawn into the chamber by having a pressure gradient betweenthe device and the chamber, wherein the chamber is at lower pressurethan the device. The volume of the chamber should approximate the tidalvolume of an inhaling patient.

Inhalable aerosol drug mass density is determined, for example, bydelivering a drug-containing aerosol into a confined chamber via aninhalation device and measuring the amount of active drug compoundcollected in the chamber. Typically, the aerosol is drawn into thechamber by having a pressure gradient between the device and thechamber, wherein the chamber is at lower pressure than the device. Thevolume of the chamber should approximate the tidal volume of an inhalingpatient. The amount of active drug compound collected in the chamber isdetermined by extracting the chamber, conducting chromatographicanalysis of the extract and comparing the results of the chromatographicanalysis to those of a standard containing known amounts of drug.

Inhalable aerosol particle density is determined, for example, bydelivering aerosol phase drug into a confined chamber via an inhalationdevice and measuring the number of particles of given size collected inthe chamber. The number of particles of a given size may be directlymeasured based on the light-scattering properties of the particles.Alternatively, the number of particles of a given size is determined bymeasuring the mass of particles within the given size range andcalculating the number of particles based on the mass as follows: Totalnumber of particles=Sum (from size range 1 to size range N) of number ofparticles in each size range. Number of particles in a given sizerange=Mass in the size range/Mass of a typical particle in the sizerange. Mass of a typical particle in a given size range=π*D³*φ/6, whereD is a typical particle diameter in the size range (generally, the meanboundary MMADs defining the size range) in microns, φ is the particledensity (in g/mL) and mass is given in units of picograms (g⁻¹²).

Rate of inhalable aerosol particle formation is determined, for example,by delivering aerosol phase drug into a confined chamber via aninhalation device. The delivery is for a set period of time (e.g., 3 s),and the number of particles of a given size collected in the chamber isdetermined as outlined above. The rate of particle formation is equal tothe number of 100 nm to 5 micron particles collected divided by theduration of the collection time.

Rate of aerosol formation is determined, for example, by deliveringaerosol phase drug into a confined chamber via an inhalation device. Thedelivery is for a set period of time (e.g., 3 s), and the mass ofparticulate matter collected is determined by weighing the confinedchamber before and after the delivery of the particulate matter. Therate of aerosol formation is equal to the increase in mass in thechamber divided by the duration of the collection time. Alternatively,where a change in mass of the delivery device or component thereof canonly occur through release of the aerosol phase particulate matter, themass of particulate matter may be equated with the mass lost from thedevice or component during the delivery of the aerosol. In this case,the rate of aerosol formation is equal to the decrease in mass of thedevice or component during the delivery event divided by the duration ofthe delivery event.

Rate of drug aerosol formation is determined, for example, by deliveringan antiparkinsonian drug containing aerosol into a confined chamber viaan inhalation device over a set period of time (e.g., 3 s). Where theaerosol is pure antiparkinsonian drug, the amount of drug collected inthe chamber is measured as described above. The rate of drug aerosolformation is equal to the amount of antiparkinsonian drug collected inthe chamber divided by the duration of the collection time. Where theantiparkinsonian drug containing aerosol comprises a pharmaceuticallyacceptable excipient, multiplying the rate of aerosol formation by thepercentage of antiparkinsonian drug in the aerosol provides the rate ofdrug aerosol formation.

Utility of Antiparkinsonian Drug Containing Aerosols

The antiparkinsonian drug containing aerosols of the present inventionare typically used for the treatment of Parkinsons.

The following examples are meant to illustrate, rather than limit, thepresent invention.

Benztropine mesylate, pergolide mesylate and amantadine were purchasedfrom Sigma (www.sigma-aldrich.com). Deprenyl hydrochloride was purchasedfrom Sigma RBI (www.sigma-aldrich.com). Ropinerole hydrochloride waspurchased as REQUIP® tablets from a pharmacy. Other antiparkinsoniandrugs can be similarly obtained.

EXAMPLE 1 General Procedure for Obtaining Free Base of a Compound Salt

Approximately 1 g of salt (e.g., mono hydrochloride) is dissolved indeionized water (˜30 mL). Three equivalents of sodium hydroxide (1 NNaOH_(aq)) is added dropwise to the solution, and the pH is checked toensure it is basic. The aqueous solution is extracted four times withdichloromethane (˜50 mL), and the extracts are combined, dried (Na₂SO₄)and filtered. The filtered organic solution is concentrated using arotary evaporator to provide the desired free base. If necessary,purification of the free base is performed using standard methods suchas chromatography or recrystallization.

EXAMPLE 2 General Procedure for Volatilizing Compounds from Halogen Bulb

A solution of drug in approximately 120 μL dichloromethane is coated ona 3.5 cm×7.5 cm piece of aluminum foil (precleaned with acetone). Thedichloromethane is allowed to evaporate. The coated foil is wrappedaround a 300 watt halogen tube (Feit Electric Company, Pico Rivera,Calif.), which is inserted into a glass tube sealed at one end with arubber stopper. Running 90 V of alternating current (driven by linepower controlled by a variac) through the bulb for 3.5 s (drug coatingof 0.01 mg to 8 mg) or for 5 s (drug coating>8 mg) affords thermal vapor(including aerosol), which is collected on the glass tube walls.Reverse-phase HPLC analysis with detection by absorption of 225 nm lightis used to determine the purity of the aerosol. (When desired, thesystem is flushed through with argon prior to volatilization.) To obtainhigher purity aerosols, one can coat a lesser amount of drug, yielding athinner film to heat. A linear decrease in film thickness is associatedwith a linear decrease in impurities.

Table 1, which follows, provides data from drugs volatilized using theabove-recited general procedure.

TABLE 1 Aerosol Argon Compound Purity Used Benztropine 98.3%  No 99.5% Yes Pergolide   98% No   98% Yes Ropinerole >90% Yes Amantadine 100% No100% Yes Deprenyl 100% No   97% Yes

EXAMPLE 3 Particle Size, Particle Density, and Rate of InhalableParticle Formation of Pergolide Aerosol

A solution of 1.3 mg pergolide in 100 μL dichloromethane was spread outin a thin layer on the central portion of a 3.5 cm×7 cm sheet ofaluminum foil. The dichloromethane was allowed to evaporate. Thealuminum foil was wrapped around a 300 watt halogen tube, which wasinserted into a T-shaped glass tube. Both of the openings of the tubewere left open and the third opening was connected to a 1 liter, 3-neckglass flask. The glass flask was further connected to a large pistoncapable of drawing 1.1 liters of air through the flask. Alternatingcurrent was run through the halogen bulb by application of 90 V using avariac connected to 110 V line power. Within 1 s, an aerosol appearedand was drawn into the 1 L flask by use of the piston, with collectionof the aerosol terminated after 6 s. The aerosol was analyzed byconnecting the 1 L flask to an eight-stage Andersen non-viable cascadeimpactor. Results are shown in table 1. MMAD of the collected aerosolwas 1.8 microns with a geometric standard deviation of 2.2. Also shownin table 1 is the number of particles collected on the various stages ofthe cascade impactor, given by the mass collected on the stage dividedby the mass of a typical particle trapped on that stage. The mass of asingle particle of diameter D is given by the volume of the particle,πD³/6, multiplied by the density of the drug (taken to be 1 g/cm³). Theinhalable aerosol particle density is the sum of the numbers ofparticles collected on impactor stages 3 to 8 divided by the collectionvolume of 1 L, giving an inhalable aerosol particle density of 6.7×10⁶particles/mL. The rate of inhalable aerosol particle formation is thesum of the numbers of particles collected on impactor stages 3 through 8divided by the formation time of 6 s, giving a rate of inhalable aerosolparticle formation of 1.1×10⁹ particles/second.

Table 1: Determination of the characteristics of a pergolidecondensation aerosol by cascade impaction using an Andersen 8-stagenon-viable cascade impactor run at 1 cubic foot per minute air flow.

Particle Average size particle Mass range size collected Number of Stage(microns) (microns) (mg) particles 0  9.0-10.0 9.5 0.01 1.3 × 10⁴ 15.8-9.0 7.4 0.02 7.5 × 10⁴ 2 4.7-5.8 5.25 0.03 3.6 × 10⁵ 3 3.3-4.7 4.00.06 1.9 × 10⁶ 4 2.1-3.3 2.7 0.10 9.8 × 10⁶ 5 1.1-2.1 1.6 0.19 8.8 × 10⁷6 0.7-1.1 0.9 0.09 2.5 × 10⁸ 7 0.4-0.7 0.55 0.04 4.0 × 10⁸ 8   0-0.4 0.20.03 6.0 × 10⁹

EXAMPLE 4 Drug Mass Density and Rate of Drug Aerosol Formation ofPergolide Aerosol

A solution of 1.0 mg pergolide in 100 μL dichloromethane was spread outin a thin layer on the central portion of a 3.5 cm×7 cm sheet ofaluminum foil. The dichloromethane was allowed to evaporate. Thealuminum foil was wrapped around a 300 watt halogen tube, which wasinserted into a T-shaped glass tube. Both of the openings of the tubewere left open and the third opening was connected to a 1 liter, 3-neckglass flask. The glass flask was further connected to a large pistoncapable of drawing 1.1 liters of air through the flask. Alternatingcurrent was run through the halogen bulb by application of 90 V using avariac connected to 110 V line power. Within seconds, an aerosolappeared and was drawn into the 1 L flask by use of the piston, withformation of the aerosol terminated after 6 s. The aerosol was allowedto sediment onto the walls of the 1 L flask for approximately 30minutes. The flask was then extracted with acetonitrile and the extractanalyzed by HPLC with detection by light absorption at 225 nm.Comparison with standards containing known amounts of pergolide revealedthat 0.3 mg of >99% pure pergolide had been collected in the flask,resulting in an aerosol drug mass density of 0.3 mg/L. The aluminum foilupon which the pergolide had previously been coated was weighedfollowing the experiment. Of the 1.0 mg originally coated on thealuminum, 1.0 mg of the material was found to have aerosolized in the 6s time period, implying a rate of drug aerosol formation of 0.2 mg/s.

1. A condensation aerosol for delivery of benzotropine formed by heating a composition containing benzotropine coated on a solid support to form a vapor and condensing the vapor to form a condensation aerosol comprising particles, wherein the particles comprise at least 10 percent by weight of benzotropine and less than 5 percent by weight of benzotropine degradation products, and the condensation aerosol has an MMAD of less than 5 microns.
 2. The condensation aerosol according to claim 1, wherein the condensation aerosol has an MMAD of 0.2 to 3 microns.
 3. The condensation aerosol according to claim 1 or claim 2, wherein the geometric standard deviation around the MMAD is less than 3.0.
 4. A condensation aerosol for delivery of pergolide formed by heating a composition containing pergolide coated on a solid support to form a vapor and condensing the vapor to form a condensation aerosol comprising particles, wherein the particles comprise at least 10 percent by weight of pergolide and less than 5 percent by weight of pergolide degradation products, and the condensation aerosol has an MMAD of less than 5 microns.
 5. The condensation aerosol according to claim 4, wherein the condensation aerosol has an MMAD of 0.2 to 3 microns.
 6. The condensation aerosol according to claim 4 or claim 5, wherein the geometric standard deviation around the MMAD is less than 3.0.
 7. A condensation aerosol for delivery of amantadine formed by heating a composition containing amantadine coated on a solid support to form a vapor and condensing the vapor to form a condensation aerosol comprising particles, wherein the particles comprise at least 10 percent by weight of amantadine and less than 5 percent by weight of amantadine degradation products, and the condensation aerosol has an MMAD of less than 5 microns.
 8. The condensation aerosol according to claim 7, wherein the condensation aerosol has an MMAD of 0.2 to 3 microns.
 9. The condensation aerosol according to claim 7 or claim 8, wherein the geometric standard deviation around the MMAD is less than 3.0.
 10. A condensation aerosol for delivery of deprenyl formed by heating a composition containing deprenyl coated on a solid support to form a vapor and condensing the vapor to form a condensation aerosol comprising particles, wherein the particles comprise at least 10 percent by weight of deprenyl and less than 5 percent by weight of deprenyl degradation products, and the condensation aerosol has an MMAD of less than 5 microns.
 11. The condensation aerosol according to claim 10, wherein the condensation aerosol has an MMAD of 0.2 to 3 microns.
 12. The condensation aerosol according to claim 10 or claim 11, wherein the geometric standard deviation around the MMAD is less than 3.0.
 13. A condensation aerosol for delivery of ropinerole formed by heating a composition containing ropinerole coated on a solid support to form a vapor and condensing the vapor to form a condensation aerosol comprising particles, wherein the particles comprise at least 10 percent by weight of ropinerole and less than 5 percent by weight of ropinerole degradation products, and the condensation aerosol has an MMAD of less than 5 microns.
 14. The condensation aerosol according to claim 13, wherein the condensation aerosol has an MMAD of 0.2 to 3 microns.
 15. The condensation aerosol according to claim 13 or claim 14, wherein the geometric standard deviation around the MMAD is less than 3.0.
 16. A method of forming a benzotropine containing aerosol comprising: (a) heating a composition containing benzotropine coated on a solid support to form a vapor; and (b) condensing the vapor to form a condensation aerosol comprising particles, wherein the particles comprise less than 5 percent by weight of benzotropine degradation products, and the condensation aerosol has an MMAD of less than 5 microns.
 17. The method according to claim 16, wherein the condensation aerosol has an MMAD of 0.2 to 3 microns.
 18. The method according to claim 17, wherein the coated composition comprises at least 10 percent by weight of benzotropine.
 19. A method of forming a pergolide containing aerosol comprising: (a) heating a composition containing pergolide coated on a solid support to form a vapor; and (b) condensing the vapor to form a condensation aerosol comprising particles, wherein the particles comprise less than 5 percent by weight of pergolide degradation products, and the condensation aerosol has an MMAD of less than 5 microns.
 20. The method according to claim 19, wherein the condensation aerosol has an MMAD of 0.2 to 3 microns.
 21. The method according to claim 20, wherein the coated composition comprises at least 10 percent by weight of pergolide.
 22. A method of forming an amantadine containing aerosol comprising: (a) heating a composition containing amantadine coated on a solid support to form a vapor; and (b) condensing the vapor to form a condensation aerosol comprising particles, wherein the particles comprise less than 5 percent by weight of amantadine degradation products, and the condensation aerosol has an MMAD of less than 5 microns.
 23. The method according to claim 22, wherein the condensation aerosol has an MMAD of 0.2 to 3 microns.
 24. The method according to claim 23, wherein the coated composition comprises at least 10 percent by weight of amantadine.
 25. A method of forming a deprenyl containing aerosol comprising: (a) heating a composition containing deprenyl coated on a solid support to form a vapor; and (b) condensing the vapor to form a condensation aerosol comprising particles, wherein the particles comprise less than 5 percent by weight of deprenyl degradation products, and the condensation aerosol has an MMAD of less than 5 microns.
 26. The method according to claim 25, wherein the condensation aerosol has an MMAD of 0.2 to 3 microns.
 27. The method according to claim 26, wherein the coated composition comprises at least 10 percent by weight of deprenyl.
 28. A method of forming a ropinerole containing aerosol comprising: (a) heating a composition containing ropinerole coated on a solid support to form a vapor; and (b) condensing the vapor to form a condensation aerosol comprising particles, wherein the particles comprise less than 5 percent by weight of ropinerole degradation products, and the condensation aerosol has an MMAD of less than 5 microns.
 29. The method according to claim 28, wherein the condensation aerosol has an MMAD of 0.2 to 3 microns.
 30. The method according to claim 29, wherein the coated composition comprises at least 10 percent by weight of ropinerole.
 31. A method of forming a drug containing aerosol comprising: (a) heating a composition containing the drug and a pharmaceutically acceptable excipient coated on a solid support to form a vapor; and (b) condensing the vapor to form a condensation aerosol comprising particles, wherein the drug is selected from the group consisting of benzotropine, pergolide, amantadine, deprenyl, and ropinerole, and wherein the particles comprise at least 10 percent by weight of the drug and less than 5 percent by weight of the drug degradation products, and the condensation aerosol has an MMAD of less than 5 microns.
 32. The method according to claim 31, wherein the condensation aerosol has an MMAD of 0.2 to 3 microns.
 33. The method according to claim 32, wherein the coated composition comprises at least 10 percent by weight of the drug.
 34. A method of forming a drug containing aerosol comprising: (a) heating a composition containing a salt form of the drug coated on a solid support to form a vapor; and (b) condensing the vapor to form a condensation aerosol comprising particles, wherein the drug is selected from the group consisting of benzotropine, pergolide, amantadine, deprenyl, and ropinerole, and wherein the particles comprise at least 10 percent by weight of the drug and less than 5 percent by weight of the drug degradation products, and the condensation aerosol has an MMAD of less than 5 microns.
 35. The method according to claim 34, wherein the condensation aerosol has an MMAD of 0.2 to 3 microns.
 36. The method according to claim 35, wherein the coated composition comprises at least 10 percent by weight of the salt form of the drug.
 37. The condensation aerosol according to claim 2, wherein the condensing comprises allowing the vapor to cool.
 38. The condensation aerosol according to claim 5, wherein the condensing comprises allowing the vapor to cool.
 39. The condensation aerosol according to claim 8, wherein the condensing comprises allowing the vapor to cool.
 40. The condensation aerosol according to claim 11, wherein the condensing comprises allowing the vapor to cool.
 41. The condensation aerosol according to claim 14, wherein the condensing comprises allowing the vapor to cool.
 42. The method according to claim 17, wherein the condensing comprises allowing the vapor to cool.
 43. The method according to claim 20, wherein the condensing comprises allowing the vapor to cool.
 44. The method according to claim 23, wherein the condensing comprises allowing the vapor to cool.
 45. The method according to claim 26, wherein the condensing comprises allowing the vapor to cool.
 46. The method according to claim 29, wherein the condensing comprises allowing the vapor to cool.
 47. The method according to claim 32, wherein the condensing comprises allowing the vapor to cool.
 48. The method according to claim 35, wherein the condensing comprises allowing the vapor to cool.
 49. A method of forming a drug containing aerosol comprising: (a) heating a composition containing the drug coated on a solid support to form a vapor, and (b) condensing the vapor to form a condensation aerosol comprising particles, wherein the drug is selected from the group consisting of benzotropine, pergolide, amantadine, deprenyl, and ropinerole, wherein the condensation aerosol is formed at a rate greater than 0.5 mg/second, and wherein the particles comprise at least 10 percent by weight of the drug and less than 5 percent by weight of the drug degradation products, and the condensation aerosol has an MMAD of less than 5 microns.
 50. The method according to claim 49, wherein the condensation aerosol has an MMAD of 0.2 to 3 microns.
 51. The method according to claim 50, wherein the condensation aerosol is formed at a rate greater than 0.75 mg/second.
 52. The method according to claim 51, wherein the condensation aerosol is formed at a rate greater than 1 mg/second.
 53. The method according to claim 52, wherein the condensation aerosol is formed at a rate greater than 2 mg/second.
 54. The method according to claim 49, wherein the condensing comprises allowing the vapor to cool. 